The sirtuins are a class of NAD+-dependent protein deacetylase enzymes that regulate a wide variety of cellular activities that promote cell survival and extend lifespan in response to environmental stress. Sirtuins exert their effect by removing acetyl groups from certain target proteins in the presence of oxidized nicotinamide adenine dinucleotide (NAD+). For example, the yeast sirtuin enzyme Sir2 (silent information regulator 2), originally identified for its role in silencing transcription of DNA, has also been shown to promote cell survival in response to caloric restriction. Similarly, in C. elegans, the sirtuin enzyme SIR-2.1 has been shown to extend lifespan. In mammalian cells, the sirtuin enzyme SIRT1 (a homolog of the yeast Sir2 and C. elegans SIR-2.1 enzymes) deacetylates the tumor suppressor p53 to promote cell survival. Sirtuins therefore appear to be activated as part of a beneficial cellular response to stress, resulting in cell survival and extended lifespan. Activators of sirtuins may therefore be beneficial in effecting fundamental cellular processes that protect cells from stress and prevent or treat age-related diseases, and lengthen healthy life.
Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is a polyphenol compound, known to be the most potent activator of sirtuins. As a stilbene phytoalexin, resveratrol continues to receive increasing attention for its role in mitigation of numerous and diverse human pathological processes including inflammation, atherosclerosis, and carcinogenesis. Resveratrol is known for its activity as an antioxidant, cyclooxygenase inhibitor, lipid modifier, platelet aggregation inhibitor and vasodilator, inhibitor of tumor initiation, promotion and progression, neuroprotector, and antiviral compound.
Resveratrol is an especially abundant component of red wines produced from grapes grown in cooler climates where plants are under stress from heavy disease pressure. Indeed, the consumption of red wine containing resveratrol is believed to be responsible for the surprisingly normal lifespan of the French, despite their heavy consumption of fatty foods that cause heart disease, a phenomenon referred to as the “French Paradox.” Resveratrol, however, is not an optimal sirtuin activator. Its practical use is also limited due to difficult isolation and stereo-selectively of extracts obtained from plant sources. More significantly, resveratrol is highly unstable due to its potential for oxidation, resulting in the formation of unstable radicals and quinones, and requiring that the final isolation of the product be carried out from impure mixtures containing multiple components.
Conventional methods of synthesizing resveratrol and resveratrol derivatives are expensive, inefficient, and do not provide for selective hydroxyl substitution. Many synthetic routes rely on Wittig and Horner-Emmons couplings that give mixtures of olefin isomers while still requiring 7-8 procedural steps. In addition, several conventional synthetic methods use methyl or benzyl ether protecting groups that require the use of boron tribromide or other inconvenient reagents for removal of those protecting groups.
In order to address the above problems, the present invention provides a novel and efficient route to synthetic resveratrol and novel derivative compounds of resveratrol having significantly improved activity and stability. Furthermore, the present invention provides a novel and efficient route to synthetic stilbene compounds.